Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia

作者：Bishton Mark J; Harrison Simon J; Martin Benjamin P; McLaughlin Nicole; James Chloe; Josefsson Emma C; Henley Katya J; Kile Benjamin T; Prince H Miles^*; Johnstone Ricky W

来源：Blood, 2011, 117(13): 3658-3668.

DOI：10.1182/blood-2010-11-318055

Histone deacetylase inhibitor (HDACI)-induced thrombocytopenia (TCP) is a major dose-limiting toxicity of this new class of drugs. Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI, we found that C57BL/6 mice treated with both the HDAC1/2-selective HDACI romidepsin and the pan-HDACI panobinostat developed significant TCP. HDACI-induced TCP was not due to myelosuppression or reduced platelet life-span, but to decreased platelet release from megakaryocytes. Cultured primary murine megakaryocytes showed reductions in pro-platelet extensions after HDACI exposure and a dose-dependent increase in the phosphorylation of myosin light chain 2 (MLC2). Phosphorylation of MLC to phospho-MLC (pMLC) and subsequent proplatelet formation in megakaryocytes is regulated by the Rho-GTPase proteins Rac1, CDC42, and RhoA. Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg-01 showed reductions in Rac1, CDC42, and RhoA protein levels after treatment with HDACIs. We were able to overcome HDACI-induced TCP by administering the mouse-specific thrombopoietin (TPO) mimetic AMP-4, which improved platelet numbers to levels similar to untreated controls. Our report provides the first detailed account of the molecular and biologic processes involved in HDACI-mediated TCP. Moreover, our preclinical studies provide evidence that dose-limiting TCP induced by HDACIs may be circumvented using a TPO mimetic. (Blood. 2011;117(13):3658-3668)

• 出版日期2011-3-31
• 单位河北医科大学